NEUROPATHIC PAIN – OPTIMIZING PATIENT OUTCOME WITH COMBINATION THERAPY

Overview OxyContin ® tablets and gabapentin (GBT) – effectiveness in neuropathic pain OXY3204 – a clinical review of OxyContin ® tablets/GBT in combination

GBT – in Neuropathic Pain 1. Gilron et al., NEJM 2005 Gabapentin Gabapentin (GBT) licensed for neuropathic pain in 2002 and available in > 50 countries GBT has proven efficacy in a range of neuropathic pain types Approximately 60% of neuropathic pain patients receive high dose GBT (≥ 1800 mg/day) 26–38% patients receive maximal doses of GBT (2207 mg/day) but not full pain resolution 1

Oxycodone – in Neuropathic Pain Oxycodone 1. Ballantyne Oncologist. 2003; 2. Dworkin et al., Arch Neurol. 2003; 3. Watson et al., Neurology 1998; 4. Watson et al., Pain 2003 Opioids have proven efficacy in neuropathic pain 1 Opioids are recommended first-line therapy for neuropathic pain 2 OxyContin® tablets provides significant reductions in global pain scores in PHN 3 OxyContin® tablets significantly reduces pain in diabetic neuropathy and improves QoL 4 OxyContin® has been licensed since 1994 and marketed since 1995 for the treatment of severe pain and is available in > 50 countries

1. Gilron et al., NEJM 2005 US diabetic neuropathy trial indicated potential added benefit Co-administration of the two drugs already exists in practice Anecdotal evidence suggests oxycodone and GBT may have additive efficacy Pre-clinical data indicates an additive benefit of GBT with opioids GBT plus opioid has been shown to provide effective pain relief at lower doses of each agent 1 GBT / Opioid Combinations

Overview OxyContin ® tablets and gabapentin (GBT) – effectiveness in neuropathic pain OXY3204 – a clinical review of OxyContin ® tablets/GBT in combination

OXY3204 A double-blind, randomized, parallel group study to compare the efficacy, safety and tolerability of prolonged-release oxycodone taken in combination with GBT, versus placebo with GBT, for treatment of moderate to severe neuropathic pain in patients with diabetes mellitus

Study Objectives Primary endpoint Secondary endpoint To evaluate the analgesic efficacy of OxyContin® tablets in combination with GBT versus GBT alone Comparison of both study arms with respect to: Use of escape medication Sleep disturbance/ sleep quality Patients’ global assessment of pain

Study Design Double-blind, randomized, parallel group Patients randomized to receive oxycodone or placebo (1:1) whilst continuing prescribed GBT All patients received OxyContin ® tablets 5 mg at study initiation – titrated stepwise to optimize analgesia Assessment Phase = for up to 12 weeks Outcome visit after 30 days

Study Design Screening 5–14 days Baseline visit n = 406 Randomisation n = 338 Placebo/GBT n = 169 Oxycodone/GBT n = 169 Week 12 Completion visit Outcome visit 30 days 12 weeks * * 7 Visits at Weeks 1, 2, 3, 4, 6, 8, 12

Entry Criteria Three month history of neuropathic pain due to diabetic neuropathy Stable diabetes – HbA1c no greater than 11% Max. Tolerated Dose (MTD) GBT for at least 1 month Moderate-to-severe pain still evident despite GBT MTD BS-11 of ≥ 5 at screening No usage of long acting opioid ≤ 1 month of screening No previous oxycodone/GBT combination exposure No long-term opioid exposure

Concomitant Medication The following were permitted: NSAIDS and tricyclic antidepressants  Only if initiated >3 weeks prior to screening and continued at stable frequency and dose Aspirin for cardiovascular indication (max. 300mg/day) Any other medication not excluded by study exclusion criteria

Patient Characteristics OxyContin ®/ GBTPlacebo/GBT Age (years) 59.7   9.9 Gender Female Male 38% 62% 33% 67% Dose of GBT patients received (%) Dose of GBT (mg/day) Optimal GBT dose

Countries, Sites, Patients CountryNo. of sitesNo. of patients screenedNo. of patients randomised Australia 343 Austria Belgium 388 Czech Republic Denmark France 143 Germany Netherlands Norway Spain Sweden 3115 Switzerland 210 UK Totals N.B. 6 and 4 patients receiving oxycodone/GBT and GBT alone, respectively were excluded post-randomisation

Patient Disposition Adverse events n = 9 (24%) Subject’s choice n = 6 (16%) Administrative n = 2 (5%) Lack of therapeutic effect n = 20 (54%) Adverse events n = 27 (64%) Subject’s choice n = 9 (21%) Administrative n = 0 (0%) Lack of therapeutic effect n = 6 (14%) Patients enrolled n = 406Screen failures n = 68 Patients randomized n = 338 Placebo n = 169 OxyContin® n = 169 Completed Study n = 128 (78%) Withdrawn n = 37 (22%) Not analyzed n = 4 (2%) Completed study n = 121 (74%) Withdrawn n = 42 (26%) Not analyzed n = 6 (4%)

Data Sets Analysed Efficacy Full analysis population – i.e. all patients who received at least one dose of study drug and had at least one primary efficacy measurement post-randomisation (n = 328)  Primary efficacy analysis i.e. Change in BS-11 Pain Scores Safety All patients receiving at least one dose of study medication and for whom one post-dose safety observation was obtained (n = 335)

Extent of Exposure Approximately 60% of patients in both treatment groups remained on 20 mg b.i.d. study medication (OxyContin ® tablets or placebo) per day

Results Primary Result: A statistically significant (p = 0.007) result in favour of the addition of oxycodone to GBT therapy Clinically relevant reduction in pain scores for OxyContin ® tablets/GBT vs. GBT alone Primary Efficacy variable: Change in BS-11 pain scores

Change in BS-11 pain score Study period OxyContin ® /GBT Placebo/GBT Change From Baseline in Mean Bs-11 Pain Scores OxyContin ® /GBT combination demonstrates significant overall treatment effect compared with Placebo/GBT p = 0.007

Secondary Efficacy Results Escape Medication Use Patients in the OxyContin ® /GBT group required statistically significantly fewer tablets of escape medication a day (p < 0.03) than GBT alone Mean escape medication (no. of tablets) Study period OxyContin ® /GBT Placebo/GBT

Secondary Efficacy Results Sleep Disturbance Patients in the OxyContin ® /GBT group recorded statistically significantly fewer nights disturbed sleep (p < 0.05) than GBT alone Median number of nights disturbed sleep Study period OxyContin ® /GBT Placebo/GBT Sleep disturbance measured over previous 7 nights to measurement

Secondary Efficacy Results Global Assessment Of Pain Relief Patients receiving OxyContin ® /GBT had significantly better pain relief than GBT alone (p = 0.003) * Patients who completed the study OxyContin ® /GBT n = 121 * Placebo/GBT n = 128 * Percentage of patients (%) Good/ very good pain relief Better/much better than pre-study medication Good/very good overall treatment of pain

Exploratory Functional Efficacy Results Pain Intensity/Score Brief pain inventory (BPI) scores: oxycodone/GBT more effective than GBT alone  Mean pain intensity and mean pain interference (p < 0.001) McGill pain questionnaire (short form): OxyContin ® tablets/GBT more effective than GBT alone  Total pain intensity score (p < 0.001)  Total sensory pain score (p < 0.001)  Total affective pain score (p < 0.001) VAS pain score for “pain last week” was statistically significantly lower (p = 0.001) for oxycodone/GBT combination Present pain intensity was statistically significantly lower (p = 0.002) compared with study initiation

Mobility  a greater percentage of OxyContin ® /GBT patients demonstrated an improvement in mobility than GBT alone (18% vs. 11%) Self care  both groups demonstrated a slight improvement in self care Usual activities  by the end of the study, more patients in both study groups were able to carry out their usual activities  in the OxyContin ® /GBT group, fewer patients remained unable to perform their usual activities compared with GBT alone Pain/discomfort  at study end, 15% OxyContin ® /GBT patients reported a reduction or absence of pain pain or discomfort compared with only 7% of patients on GBT alone Anxiety/depression  by study end, the percentage of patients reporting they were not anxious or depressed increased by 18% in the OxyContin ® /GBT group compared with an increase of only 10% with GBT Patient resource utilisation  very few patients in either group used additional health care resources between visits Exploratory Functional Efficacy Results EuroQoL EQ-5D

Safety Overall, treatment-emergent adverse events (AEs) were more frequently reported in patients in the OxyContin ® /GBT group (88%) compared to patients receiving GBT (71%) The most frequently reported AEs in the OxyContin ® /GBT group were recognised opiate/induced AEs:  constipation (27%)  nausea (26%)  vomiting (10%)  fatigue (18%)  dizziness (15%)  headache (10%)  somnolence (22%) SAEs were experienced by a comparable number in each group (oxycodone/GBT n = 19; Placebo/GBT n = 18) There was one non-treatment-related death in the OxyContin ® /GBT group (MI)

Safety The majority of the treatment-emergent AEs were mild or moderate  Patients receiving OxyContin ® /GBT experienced more AEs associated with opioids versus GBT alone (constipation and nausea)  AEs designated to be related to study treatment were all opiate-related (constipation, nausea, fatigue, dizziness and somnolence) AEs were not exacerbated by the addition of OxyContin ® tablets to GBT therapy

Conclusions This study provides the first evidence that the addition of prolonged- release oxycodone to GBT therapy can improve outcomes for patients with diabetic neuropathy OxyContin ® plus GBT statistically and clinically significantly reduces patient pain scores The difference between OxyContin ® /GBT and GBT alone is statistically significant Secondary and exploratory efficacy variables confirm the beneficial effect of OxyContin ® /GBT for patients with diabetic neuropathy Importantly, AEs were not exacerbated by the addition of OxyContin ® tablets to GBT therapy

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